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Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents

journal homepage: www.elsevier.com/locate/ijantimicag

Dual therapy with dolutegravir plus boosted protease inhibitor as

maintenance or salvage therapy in highly experienced people living
with HIV
Yu-Lin Lee a,b,c, Kuan-Yin Lin d, Shu-Hsing Cheng e, Po-Liang Lu f, Ning-Chi Wang g,
Mao-Wang Ho h, Chia-Jui Yang i,j, Bo-Huang Liou k, Hung-Jen Tang l,m, Shie-Shian Huang n,
Sung-Hsi Huang o,p, Tun-Chieh Chen f,q, Chi-Ying Lin r, Shih-Ping Lin s, Yuan-Ti Lee c,t,∗,
Chien-Ching Hung p,u , on behalf of the Taiwan HIV Study Group
a
Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
b
Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung City, Taiwan
c
School of Medicine, Chung Shan Medical University, Taichung, Taiwan
d
Department of Medicine, National Taiwan University Hospital Jin-Shan Branch, New Taipei City, Taiwan
e
Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
f
Department of Internal Medicine, Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
g
Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
h
Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
i
Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
j
School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
k
Department of Internal Medicine, Hsinchu MacKay Memorial Hospital, Hsinchu, Taiwan
l
Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
m
Department of Health and Nutrition, Chia Nan University of Pharmacy and Sciences, Tainan, Taiwan
n
Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
o
Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
p
Department of Tropical Medicine and Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan
q
Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
r
Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan
s
Section of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
t
Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
u
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Real-world experience with dolutegravir (DTG) plus boosted protease inhibitor (bPI) as a two-drug regi-
Received 1 January 2021 men is limited for highly experienced HIV-positive patients with virological failure or intolerance to an-
Accepted 3 July 2021
tiretroviral therapy. Patients receiving DTG plus bPI between September 2016 and June 2019 at 15 des-
Available online xxx
ignated hospitals for HIV care in Taiwan were retrospectively included in this study. A standardised case
Editor: Professor Philippe Colson record form was used to collect clinical data. The primary endpoint was virological response, defined
as achieving or maintaining plasma HIV-RNA <50 copies/mL at Week 48. A total of 77 patients were
Keywords:
included; 58 (75.3%) had documented genotypic resistance to 1–4 antiretroviral classes. The most com-
Integrase strand transfer inhibitor
Two-drug regimen monly used PI was darunavir (87.0%; 67/77). Seven patients (9.1%) had no virological data at Week 48,
Antiretroviral resistance including three with loss to follow-up, one severe hyperlipidaemia, one renal failure and cardiovascular
Weight gain disease, one superimposed HBV infection and one death from anal cancer. The virological response rate
Dyslipidaemia increased from 59.7% at baseline to 90.9% at Week 24 and 85.7% at Week 48. The only patient (1.3%) with
virological failure at Week 48 had poor adherence and baseline low-level resistance to darunavir with
resistance-associated mutations at M46L, I50V and V82A. Compared with baseline, mean total cholesterol
increased by 20.1 mg/dL and weight by 2.8 kg at Week 48, while the estimated glomerular filtration rate
decreased by 14.4 mL/min/1.73m2 (both P < 0.05). We conclude that a two-drug regimen containing DTG
plus bPI was effective in highly-experienced HIV-positive patients, but metabolic impact and weight gain
should be closely monitored.
© 2021 Published by Elsevier Ltd.

https://doi.org/10.1016/j.ijantimicag.2021.106403
0924-8579/© 2021 Published by Elsevier Ltd.

Please cite this article as: Y.-L. Lee, K.-Y. Lin, S.-H. Cheng et al., Dual therapy with dolutegravir plus boosted protease inhibitor as
maintenance or salvage therapy in highly experienced people living with HIV, International Journal of Antimicrobial Agents, https:
JID: ANTAGE
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Y.-L. Lee, K.-Y. Lin, S.-H. Cheng et al.
1. Introduction
Since the first antiretroviral drug, zidovudine, was used for
treatment of human immunodeficiency virus (HIV) infection in
1987, more than 30 antiretroviral agents in seven mechanistic
classes have been approved by the US Food and Drug Adminis-
tration (FDA). In most HIV treatment guidelines, the first-line an-
tiretroviral regimens generally consist of two nucleoside reverse
transcriptase inhibitors (NRTIs) plus a third agent from the in-
tegrase strand transfer inhibitors (INSTIs), non-nucleoside reverse
transcriptase inhibitors (NNRTIs) or boosted protease inhibitors
(bPIs) [1–3].
With the introduction of new antiretroviral drugs with greater
potency and higher genetic barrier to the emergence of resistance-
associated mutations (RAMs) in the recent decade, NRTI-sparing or
NRTI-reducing two-drug regimens have been evaluated as an al-
ternative treatment for antiretroviral-naïve or antiretroviral-treated
patients [4–7]. In the GEMINI studies, dolutegravir (DTG) plus
lamivudine (3TC) demonstrated non-inferior efficacy and a simi-
lar tolerability profile to DTG plus tenofovir disoproxil fumarate
(TDF)/emtricitabine (FTC) in antiretroviral-naïve adults with HIV-
1 infection [8]. In the NEAT 001/ANRS 143 trial, ritonavir-boosted
darunavir (DRV/r) plus raltegravir (RAL) also demonstrated non-
inferiority to DRV/r plus TDF/FTC in antiretroviral-naïve adults [9].
Two-drug regimens, such as DTG plus rilpivirine in the SWORD
trials and DTG plus 3TC in the TANGO trial, were recently shown
to be non-inferior to comparators of conventional three-drug reg-
imens among HIV-positive patients with HIV suppression [10,11].
However, the participants in these trials had been on stable
antiretroviral therapy (ART) without prior virological failures or
RAMs. Whether these regimens can be used in patients with mul-
tiple failures or intolerance remains unclear.
The Department of Health and Human Services (DHHS) guide-
lines for the use of antiretroviral agents in HIV-positive adults and
adolescents recommend that a salvage regimen should include at
least two, and preferably three, fully active agents. For heavily ex-
perienced HIV-positive patients with virological failure, a bPI plus
an INSTI is a therapeutic option [1]. A combination of ritonavir-
boosted lopinavir (LPV/r) plus RAL was proven to be non-inferior
to the regimen of LPV/r plus two or three NRTIs in the SECOND-
LINE study [12]. A two-drug regimen including a new INSTI, such
as DTG, plus a bPI is also suggested in the DHHS guidelines [1],
however the supporting evidence is limited [12].
In this multicentre retrospective study, we aimed to evaluate
the effectiveness and tolerability of DTG plus bPI as salvage ther-
apy or maintenance therapy for highly experienced HIV-positive
patients.
2. Methods
2.1. Study design and patients
This was a multicentre study conducted at 15 designated hospi-
tals that provide medical care to HIV-positive patients around Tai-
wan. Between September 2016 and June 2019, patients aged ≥20
years who had been receiving DTG plus a bPI for more than 3
months were included. Patients with hepatitis B virus (HBV) in-
fection were excluded if they were unable to take any effective
anti-HBV agents such as entecavir, TDF or tenofovir alafenamide
(TAF). A standardised case record form was used to collect infor-
mation on the demographics and clinical characteristics of the pa-
∗
Corresponding author. Mailing address: School of Medicine, Chung Shan Medi-
cal University, Number 110, Section 1, Jianguo N. Road, Taichung City 40201, Taiwan.
Tel.: +886 4 2473 9595 ext. 34708; fax: +886 4 2324 8134.
E-mail address: leey521@gmail.com (Y.-T. Lee).
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International Journal of Antimicrobial Agents xxx (xxxx) xxx
tients at baseline and during follow-up, including age, sex, sex-
ual orientation and weight. According to the national HIV treat-
ment guidelines in Taiwan, all HIV-positive patients at the desig-
nated hospitals are followed at least every 3 months and labora-
tory tests are performed every 3–6 months, which includes plasma
HIV-RNA load, CD4 T-lymphocyte count, renal function, liver func-
tion, lipid profile and glucose levels. ART and laboratory monitor-
ing are provided free of charge at designated hospitals around Tai-
wan. While genotypic resistance testing was not mandatory before
switch of ART in Taiwan, we collected available data on RAMs for
the included patients at each hospital. Genotypic resistance test-
ing was carried out as previously described [13,14]. The study was
approved by the Research Ethics Committees or Institutional Re-
view Boards of the 15 participating hospitals. The requirement for
informed consent was waived.
2.2. Study endpoints
The primary outcome was the proportion of virological re-
sponse of the included patients at Week 48. Virological response
was defined as plasma HIV-RNA <50 copies/mL; low-level viraemia
was defined for patients with confirmed plasma HIV-RNA level of
50–199 copies/mL; and no virological data was defined for patients
with lack of virological data for any reason including death, loss to
follow-up, transfer of care or switch to other regimens. Virological
failure was defined as plasma HIV-RNA ≥200 copies/mL. Assess-
ment windows of virological response at Week 24 and Week 48
were ±2 weeks. Secondary outcomes included virological response
at Week 24 and changes in lipids, weight and estimated glomeru-
lar filtration rate (eGFR) from baseline. eGFR was calculated by the
Modification of Diet in Renal Disease (MDRD) equation.
For patients who had maintained a good virological re-
sponse, we used a modified FDA snapshot algorithm and a next
observation-carried-backward approach to extend the assessment
window for patients who missed their HIV-RNA testing at Week
24 and Week 48, as previously described [15]. The decision to con-
tinue or to switch ART in light of virological non-response or ad-
verse effects was at the discretion of the treating physicians. The
reasons for discontinuation or switch were recorded.
2.3. Statistical analyses
Data were analysed using IBM SPSS Statistics v.19.0 (IBM Corp.,
Armonk, NY, USA). Continuous variables, including age, duration
of previous ART, body weight, eGFR and CD4 T-lymphocyte count,
were described as the median and interquartile range. A non-
parametric test of cholesterol, triglycerides, eGFR and body weight
at all three time points was performed by repeated measures anal-
ysis of variance (ANOVA) with pairwise comparisons. However, the
differences in parameters between follow-up and baseline data
were presented as mean values in order to compare with other
published studies. Categorical data were analysed using the χ 2 test
or Fisher’s exact test. The power of the study was also calculated
by post-hoc analysis based on virological response rates at Week
24 and Week 48. All tests were two-tailed, and a P-value of <0.05
was considered statistically significant.
3. Results
3.1. Study population
A total of 77 eligible patients were included in this mul-
ticentre study. The baseline characteristics of the included pa-
tients are shown in Table 1. The median age was 36.0 years and
most patients (96.1%) were male. All patients were antiretroviral-
experienced with exposure to previous ART for a median duration
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Table 1
Baseline characteristics of patients (N = 77) switching to dolutegravir (DTG) plus boosted protease inhibitors
(bPI)
a
Characteristic n (%)

Age (years) [median (IQR)] 36.0 (30.0–44.5)

Male sex 74 (96.1)
HBV co-infection 3 (3.9)
Duration of ART use before switch to DTG + bPI (months) [median (IQR)] 48.0 (21.0––79.0)
Use of RAL + bPI before switching to DTG + bPI 35 (45.5)
Duration of RAL + bPI before switching to DTG + bPI (months) [median (IQR)] 26.2 (13.5–33.0)
Reasons for switching to DTG + bPI
Resistance 36 (46.8)
Drug simplification 27 (35.1)
Intolerance to previous ART b 10 (13.0)
Co-morbidities c 4 (5.2)
bPIs used to combine with DTG
DRV/r 65 (84.4)
DRV/c 2 (2.6)
ATV/r 5 (6.5)
LPV/r 5 (6.5)
Baseline body weight before switch (kg) [median (IQR)] 65.0 (60.0–74.8)
Baseline eGFR before switch (mL/min/1.73m2 ) [median (IQR)] 104.4 (90.7–121.5)
Baseline plasma HIV-RNA <20 copies/mL 40 (51.9)
Baseline CD4 T-lymphocyte count before switch (cells/mm3 ) [median (IQR)] 381 (154.5–610.5)
Baseline ART before switch to DTG plus bPI
XTC/TDF 30 (39.0)
XTC/ABC 13 (16.9)
XTC/ZDV 32 (41.6)
3TC/d4T 2 (2.6)
RAL 6 (7.8)
DTG 7 (9.1)
ATV 4 (5.2)
ATV/r 9 (11.7)
DRV/r 15 (19.5)
LPV/r 17 (22.1)
TPV/r 1 (1.3)
EFV 8 (10.4)
NVP 6 (7.8)
RPV 5 (6.5)
T20 2 (2.6)

IQR, interquartile range; HBV, hepatitis B virus; ART, antiretroviral therapy; eGFR, estimated glomerular
filtration rate; 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; ATV/r, ritonavir-boosted atazanavir; d4T,
stavudine; DRV/c, cobicistat-boosted darunavir; DRV/r, ritonavir-boosted darunavir; EFV, efavirenz; LPV/r,
ritonavir-boosted lopinavir; NVP, nevirapine; RAL, raltegravir; RPV, rilpivirine; T20, enfuvirtide; TDF, teno-
fovir disoproxil fumarate; TPV/r, ritonavir-boosted tipranavir; XTC, lamivudine or emtricitabine; ZDV, zidovu-
dine.
a
Data are n (%) unless otherwise stated.
b
Intolerance: TDF/3TC allergy (4), ZDV-related anaemia (4), myalgia and arthralgia (1) and diarrhoea (1).
c
Co-morbidities: renal failure (2) and cardiovascular disease (2).

of 48 months before switch to DTG plus bPI. The main reason for
switch to DTG plus bPI was emergence of resistance that led to
treatment failures with previous ART regimens (n = 36; 46.8%),
followed by other reasons included drug simplification (n = 27;
35.1%), antiretroviral intolerance (n = 10; 13.0%) and emerging
co-morbidities (n = 4; 5.2%). Approximately one-half of the pa-
tients (n = 35; 45.5%) had received RAL plus bPI before switch-
ing to DTG plus bPI, with a median duration of 26.2 months. Most
patients were switched to DRV/r or cobicistat-boosted darunavir
(DRV/c) in combination with DTG (n = 67; 87.0%); other bPIs in-
cluded ritonavir-boosted atazanavir (ATV/r) (n = 5; 6.5%) and LPV/r
(n = 5; 6.5%). All patients had been followed-up and undergone
blood testing at Week 24. Seven patients had no virological data
at Week 48: three were lost to follow-up (two being incarcerated),
one died of anal cancer, one had superimposed HBV infection for
which TDF was added, one had severe hyperlipidaemia and one
had renal failure and cardiovascular disease.
3.2. Virological outcomes
Virological responses after switch at Week 24 and Week 48 are
shown in Fig. 1. Before switch to DTG plus bPI, 22 patients (28.6%)
had plasma HIV-RNA ≥200 copies/mL and 9 patients (11.7%) had
low-level viraemia. At Week 24, 70 patients (90.9%) achieved viral
suppression, 4 (5.2%) had low-level viraemia and 3 (3.9%) had vi-
rological failure. The four patients with low-level viraemia at Week
24 included one patient with plasma HIV-RNA <50 copies/mL and
three patients with low-level viraemia at baseline. The three pa-
tients with virological failure at Week 24 were those who had
plasma HIV-RNA ≥200 copies/mL at baseline. The first patient had
irregular adherence. His plasma HIV-RNA was 64 544 copies/mL
before switch, which decreased to 21 copies/mL at 1 month af-
ter treatment with DTG plus bPI; however, plasma HIV-RNA re-
bounded to 10 8042 copies/mL at Week 24. He was subsequently
lost to follow-up and no more data on plasma HIV-RNA were
available at Week 48. The second patient was incarcerated for
3 months. The plasma HIV-RNA was 557 0 0 0 copies/mL initially,
which decreased to 411 copies/mL at Week 24. The patient was
adherent to DTG plus bPI after release from prison and achieved
viral suppression at Week 48. The third patient had poor adher-
ence throughout the whole observation period. The plasma HIV-
RNA was 31 100, 18 000 and 57 500 copies/mL at Weeks 0, 24
and 48, respectively. All three patients had multiple RAMs before
switch. Detailed data are given in Supplementary Tables S1 and S2.

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Fig. 1. Virological response at baseline (W0), Week 24 (W24) and Week 48 (W48). Virological suppression was defined as plasma HIV-RNA <50 copies/mL, virological
failure was defined as plasma HIV-RNA ≥200 copies/mL; low-level viraemia was denied as patients with confirmed detectable HIV-RNA level of 50–199 copies/mL; and no
virological data was defined as patients with lack of virological data for any reason.

At Week 48, the rate of virological suppression was 85.7% Table 2

Major resistance-associated mutations of HIV-1 from 62 patients with genotyping
(66/77); virological non-response was noted in 4 patients (5.2%),
performed before switch to dolutegravir plus boosted protease inhibitor
with 1 (1.3%) having virological failure and 3 having low-level vi-
raemia; and 7 patients (9.1%) had no virological data (Fig. 1). The Major resistance-associated mutation n (%)
only patient (1.3%) with virological failure at Week 48 had poor ad- Nucleoside reverse transcriptase inhibitors
herence and baseline low-level resistance to DRV. In the post-hoc K65R 31 (50.0)
analysis, the power of our study based on the virological response K70R 8 (12.9)
L74I, L74V 6 (9.7)
rates at Week 24 and Week 48 were 99.3% and 95.0%, respectively.
M184V, M184I 32 (51.6)
Of the 46 patients who had had virological suppression before Y115F 2 (3.2)
switch to DTG plus bPI, 45 (97.8%) and 41 (89.1%) remained viro- M41L 6 (9.7)
logically suppressed at Week 24 and Week 48, respectively, with 1 D67G, D65N 12 (19.4)
L210W 6 (9.7)
patient having low-level viraemia at Week 24, and 2 patients hav-
T215F, T215Y 15 (24.2)
ing low-level viraemia and 3 having no virological data at Week K219E, K219Q 12 (19.4)
48. Non-nucleoside reverse transcriptase inhibitors
Of the 22 patients with plasma HIV-RNA ≥200 copies/mL before L100I 6 (9.7)
switch to DTG plus bPI, 19 (86.4%) achieved virological suppression K101E, K101P 6 (9.7)
K103N, K103S 18 (29.0)
and 3 (13.6%) had plasma HIV-RNA ≥200 copies/mL at Week 24.
V106A, V106M, V106I 10 (16.1)
At Week 48, 17 patients (77.3%) achieved virological suppression, 1 Y181C, Y181I 18 (29.0)
(4.5%) had virological failure and 4 (18.2%) had no virological data. G190A, G190S, G190E 13 (21.0)
Of the 35 patients who were receiving RAL plus bPI before Protease inhibitors
M46L 1 (1.6)
switch, 8 had detectable HIV-RNA (median plasma HIV-RNA, 3599
I50L, I50V 3 (4.8)
copies/mL) at baseline, all of whom achieved virological suppres- V82A 1 (1.6)
sion at Week 48. L10I, L10V 8 (12.9)
A71T, A71V 9 (14.5)
Integrase strand transfer inhibitors a
3.3. Antiretroviral resistance before switch T66A 1 (3.8)
E92Q 1 (3.8)
a
Information on RAMs from 62 patients with available genotypic Integrase strand transfer inhibitor resistance profiles were only available for 26
resistance testing results are shown in Table 2. The most common patients.

NRTI RAMs were M184V/I (51.6%; 32/62), K65R (50.0%; 31/62) and
thymidine analogue mutations including T215F/Y (24.2%; 15/62)
and K219E/Q (19.4%; 12/62). The most common NNRTI RAMs were
Y181C/I (29.0%; 18/62) and K103N/S (29.0%; 18/62).
PI RAMs were uncommon. Only one patient had HIV-1 har-
bouring mutations including M46L, I50V and V82A that confer
intermediate-level resistance to DRV. The patient was also the only
patient who had virological failure at Week 48. In addition, I50L
mutation was found in another two patients with atazanavir resis-
tance, which had no impact on susceptibility to boosted DRV. INSTI
RAMs were determined for 26 patients who had experience with
any INSTI before switch. Two patients had INSTI RAMs, including
one with T66A and another with E92Q. Both mutations had mini-
mal or no impact on susceptibility to DTG. The patient with T66A
had virological suppression at Week 24 but low-level viraemia at
Week 48. The other patient with E92Q maintained virological sup-
pression at both Week 24 and Week 48.
3.4. Changes in biochemical parameters and weight after switch
Changes in total cholesterol, triglycerides, eGFR and weight
are illustrated in Fig. 2. One-way repeated measures ANOVA
showed significant changes for total cholesterol, eGFR and weight
(P = 0.046, <0.001 and <0.001, respectively) but not for triglyc-
erides (P = 0.897). Pairwise comparisons revealed significant differ-
ences in weight between Week 0 and both Week 24 and Week 48.
Differences in eGFR were noted between Week 0 and both Week
24 and Week 48, but not between Week 24 and Week 48. For
cholesterol, no significant differences were noted in pairwise com-

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Fig. 2. Changes of (A) total cholesterol, (B) triglycerides, (C) estimated glomerular filtration rate and (D) body weight at baseline, Week 24 and Week 48.
one-way repeated measures ANOVA.
parisons. The results of linear trend analysis were significant for
eGFR (P < 0.001) and weight (P < 0.001) but not for cholesterol
(P = 0.0624) and triglycerides (P = 0.8982).
At Week 48, total cholesterol level increased by 20.1 mg/dL
from baseline (P < 0.001) (Fig. 2A). However, the triglyceride level
showed no significant changes throughout follow-up (Fig. 2B). The
mean low-density lipoprotein cholesterol (LDL-C) level increased
from 96.8 mg/dL at baseline to 123.8 mg/dL at Week 48 (dif-
ference, 27.0 mg/dL; P < 0.001), while the high-density lipopro-
tein cholesterol (HDL-C) level showed no statistically significant
changes.
The mean eGFR was 105.0 mL/min/1.73m2 before switch, which
decreased to 94.1 mL/min/1.73m2 at Week 24 (difference, 10.9
mL/min/1.73m2 ; P < 0.001) (Fig. 2C) and 90.6 mL/min/1.73m2 at
Week 48 (difference, 14.4 mL/min/1.73m2 ; P < 0.001) (Fig. 2C).
There were no significant changes in the aminotransferase levels,
total bilirubin levels or complete blood cell counts. Data on weight
changes were available for 69 patients. The average weight in-
creased from 68.6 kg to 69.9 kg at Week 24 (difference, 1.3 kg; P
< 0.001) and to 71.4 kg at Week 48 (difference, 2.8 kg; P < 0.001)
(Fig. 2D).
3.5. Safety
Two patients (2.6%) discontinued DTG plus bPI owing to ad-
verse effects. One patient had severe hyperlipidaemia while receiv-
ing DTG plus ATV/r and was switched to DTG plus 3TC after 9
months of DTG and ATV/r. The other patient had insomnia due
to DTG and jaundice due to ATV/r and the regimen was subse-
quently switched to co-formulated elvitegravir, cobicistat, FTC, and
TAF plus DRV after 14 months.
4. Discussion
In this study, combination of DTG plus bPI (mostly boosted
DRV) was evaluated as an option for highly experienced HIV-
positive patients, especially those who had multiple antiretroviral
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International Journal of Antimicrobial Agents xxx (xxxx) xxx
∗
P < 0.05 for
RAMs or intolerance to prior regimens. We found that only one pa-
tient had virological failure due to non-adherence, although seven
patients had no virological data at Week 48. After switch, total
cholesterol and weight increased, while eGFR decreased.
The SECOND-LINE study revealed that RAL plus LPV/r was as ef-
fective as two NRTIs plus LPV/r among patients who experienced
virological failure on an NNRTI-based regimen [12,16,17]. However,
a two-drug regimen including DTG plus bPI as a second-line reg-
imen has had limited experience until recently when the DUALIS
trial demonstrated that switch to DTG plus boosted DRV was non-
inferior to two NRTIs plus boosted DRV [18], with similar rates
of plasma HIV-RNA ≥50 copies/mL at Week 48 [1.6% (2/131) vs
3.1% (4/132)]. The rate of virological failure in our study at Week
48 (1.3%; 1/77) was in line with that observed in the DUALIS
trial. However, the DUALIS trial enrolled patients with plasma HIV-
RNA <50 copies/mL after taking two NRTIs plus boosted DRV for
≥24 weeks; in contrast, 40.3% (31/77) of patients in our study
had plasma HIV-RNA ≥50 copies/mL before switch to DTG plus
bPIs. DTG plus bPI was well tolerated in our study and the dis-
continuation rate was 2.6% (2/77), similar to that observed in
the DUALIS trial (4.6%). Virological response with DTG plus bPI
in our study was also similar to that in the study by Capetti
et al. that investigated the effectiveness of DTG plus DRV/r for
rescue or simplification of rescue therapy and revealed that 76.2%
(99/130) of the included patients achieved undetectable viral load
and 14.6% (19/130) had plasma HIV-RNA between 1 copy/mL and
49 copies/mL at Week 48 [19].
PIs have been shown to be associated with abnormal serum
lipoprotein concentrations [20–22]. Patients receiving DTG plus bPI
in our study had dyslipidaemia with increased total cholesterol
and LDL-C levels, but with no significant changes in HDL-C lev-
els. The occurrence of dyslipidaemia in this population with lim-
ited antiretroviral options indicates that regular monitoring of lipid
profiles and lifestyle modifications such as smoking cessation, diet
control and exercise should be recommended. Addition of lipid-
lowering agents should also be considered, especially for patients
at high cardiovascular risk.
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Weight gain is an emerging issue among patients receiving
ART in recent years. The North American AIDS Cohort Collabora-
tion on Research and Design (NA-ACCORD) revealed that patients
starting INSTI-based and PI-based regimens had a mean estimated
5-year weight gain of 5.9 kg and 5.5 kg compared with 3.7 kg
for NNRTI-based regimens [23]. A recent study in Taiwan showed
a mean weight gain of 1.75 kg at Week 48 after switch to co-
formulated elvitegravir, cobicistat, FTC and TAF among 693 viro-
logically suppressed HIV-positive patients [24]. The newer INSTIs,
DTG and bictegravir, were recently shown to be associated with
greater weight gain than elvitegravir/cobicistat [25]. In our study,
we observed a weight increase of 1.3 kg and 2.8 kg at Week 24 and
Week 48, respectively, with switch to DTG plus bPI from regimens
of RAL plus bPI, two NRTIs plus NNRTI, and two NRTIs plus bPI.
While the cause of weight gain is multifactorial in nature and the
mechanism requires further investigation, overweight and obesity
are well known to contribute to cardiometabolic complications in-
cluding atherothrombotic cardiovascular disease and diabetes mel-
litus [26]. It is important to monitor weight regularly and to keep
a healthy lifestyle, especially among those with overweight or obe-
sity.
In this study, we found increased levels of serum creatinine and
decreased eGFR. However, the decrease of eGFR did not indicate
true deterioration of renal function. DTG inhibits organic cation
transporter 2 (OCT2) on the proximal renal tubule cells [27] and
blocks the tubular uptake of creatinine, a substrate of OCT2, from
the blood leading to increases in its serum level [28]. As the eGFR
is estimated by serum creatinine level, use of DTG causes un-
derestimation of the true GFR. In the SPRING-2 study, the mean
eGFR decreased by 16.5 mL/min/1.73m2 in the DTG group at the
end of 48 weeks [29]. In our study, the eGFR decreased by 10.9
mL/min/1.73m2 and 14.4 mL/min/1.73m2 at Week 24 and Week
48, respectively. The trend was also similar to that of an obser-
vational study in Taiwan in which switch of PI-based regimens to
DTG plus two NRTIs was associated with a significant decline of
eGFR at Week 48 (–18.2 mL/min/1.73m2 ) [30].
There are several limitations of this study. First, this was a
single-arm retrospective cohort study conducted in settings where
accessibility to resistance testing and newer antiretroviral agents
was limited when the study was started in Taiwan. Second, the
decision to choose DTG plus bPI was made by the treating physi-
cians. While there were no data on adherence, it is likely that pa-
tients who were adherent were considered suitable for switch to
DTG plus bPI. The results may not be generalisable to those who
are not adherent to the ART administered. Third, the follow-up in-
tervals for virological responses were at the discretion of the treat-
ing physicians and were not as frequent as those in clinical trials.
Fourth, the case number remained small and the observation dura-
tion short. More studies of longer observation duration are needed
to confirm our findings.
In conclusion, we demonstrated that DTG plus bPI (mainly
boosted DRV) was effective in highly experienced HIV-positive pa-
tients with multiple antiretroviral resistance. Given the findings of
weight gain and metabolic derangement after switch to DTG plus
bPI, identification of newer regimens capable of maintaining viro-
logical response with a favourable metabolic profile is warranted.
Funding
Y-TL received a grant from Chung Shan Medical University Hos-
pital, Taiwan [Number: CSH-2020-C-011]. The funder played no
role in the design of the study, analysis, interpretation of data,
writing of the manuscript, and the decision to submit it for publi-
cation.
Competing interests: C-CH has received research support from
Janssen, Merck, Gilead Sciences and ViiV, has received speaker’s
6
[m5G;August 4, 2021;14:32]
International Journal of Antimicrobial Agents xxx (xxxx) xxx
honoraria from AbbVie, Bristol-Myers Squibb, Gilead Sciences and
ViiV and has served on advisory boards for Gilead Sciences,
Janssen, ViiV and AbbVie. All other authors declare no competing
interests.
Ethical approval: The study was approved by the Research
Ethics Committees or Institutional Review Boards of the 15 par-
ticipating hospitals. The requirement for informed consent was
waived.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.ijantimicag.2021.
106403.
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